Friday, 15 January 2016

The Dangers of Drug Development

News story is breaking about terrible side effects occurring as a result of some drug testing.(Link). The story is suggesting that this cannabis trial (Phase I) for an agent that is a pain killer. This is highly unlikely that it is cannabis and this has been denied already (link), but it may be a synthetic. However, as so many people are affected including one person who is brain dead..we will have to see how much human error is involved as a result of the "Elephant head" problem when all people were dosed with an anti-CD28 agent at the same time.People got a cytokine storm that shut down their blood vessels and so people lost their fingers and toes but by the time the first person had symptoms it was too late as the others had been dosed.Whilst this is not MS directly it does show the risks of developing drugs. This is a tragic event for those involved and we wish for aspeedy recovery for the remaining people.

Update:It is suggested the drug is BIA-10-2474 by Bial pharmaceuticals (LINK). The suggestion is that this is a Fatty Amide Hydrolase Inhibitor (FAAH). This breaks down anandamide, which is the natural cannabinoid that we produce. This stimulates the cannabinoid and other receptors and channels and so blocking Fatty Acid Amide Hydrolase will increase anandamide in the brain and and so could inhibit pain. It could also inhibit spasticity as we have showed in the past.One FAAH inhibitor by Pfizer was in phase II trials in pain and it failed to show efficacy, others have failed toxicology, so it is not a target without problems. In rodents there is only one molecule called FAAH-1 but in humans there are two molecules FAAH-1 and FAAH-2, and am not sure what are the distinct functions that these molecules have.

However the target has problems, which I think would limit its use

The liver produces a lot of FAAH. I suspect that it is involved in metabolism of fats within the liver and FAAH inhibition could make the liver turn to frois gras (fatty liver) in some strains, so maybe there has been liver failure, which could lead glutamine and ammonia production and lead to brain oedema and this would result in coma/brain death. This is a hypothesis we will find out in time. In animals it may take time for liver problems to show themslves but in humans there have had years to potentially cause them.As said before FAAH-inhibitors have been used in humans before and it posssible that this is an off-target effect as the cannabinoids tend to hit more than one target..JNJ-4216427 and apparently MF-4409 (apparently) underwent phase I multiple dose testing completed at the end of 2014 and 2009, what happened next? Why no phase II?PF-04457845 which inhibted FAAH by about 97% underwent phase II trial.

How many others didnt make it?UpdateIt appears that person with brain death has now died. (link), so one imagines a post-mortem will document what the problem was.

4 comments:

This is very sad those poor people and their families. I am not looking forward to the talking heads on this issue. How long will it take for a Dr captain hindsight to get on the TV and say 'any first year immunology student could have predicted this etc!'

I'm living in Rennes (where this very sad accident just happened). As Aidan mentionned, we here already hear people who seem to know everything on earth. Add to this the tradional public-vs-private debate, the pharma-acting-without-any-public-control ... So the answer is : "Not so long"

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